Independent β-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2

Huijun Wei, Seungkirl Ahn, Sudha K. Shenoy, Sadashiva S. Karnik, L. Hunyady, Louis M. Luttrell, Robert J. Lefkowitz

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Abstract

Stimulation of a mutant angiotensin type 1A receptor (DRY/AAY) with angiotensin II (Ang II) or of a wild-type receptor with an Ang II analog ([sarcosine1, Ile4, Ile8]Ang II) fails to activate classical heterotrimeric G protein signaling but does lead to recruitment of β-arrestin 2-GFP and activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (maximum stimulation ≈50% of wild type). This G protein-independent activation of mitogen-activated protein kinase is abolished by depletion of cellular β-arrestin 2 but is unaffected by the PKC inhibitor Ro-31-8425. In parallel, stimulation of the wild-type angiotensin type 1A receptor with Ang II robustly stimulates ERK1/2 activation with ≈60% of the response blocked by the PKC inhibitor (G protein dependent) and the rest of the response blocked by depletion of cellular β-arrestin 2 by small interfering RNA (β-arrestin dependent). These findings imply the existence of independent G protein- and β-arrestin 2-mediated pathways leading to ERK1/2 activation and the existence of distinct "active" conformations of a seven-membrane-spanning receptor coupled to each.

Original languageEnglish
Pages (from-to)10782-10787
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number19
DOIs
Publication statusPublished - Sep 16 2003

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Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
GTP-Binding Proteins
Angiotensin II
Angiotensin Type 1 Receptor
Arrestin
Heterotrimeric GTP-Binding Proteins
Angiotensin Receptors
Mitogen-Activated Protein Kinases
Small Interfering RNA
Membranes
beta-Arrestin 1

ASJC Scopus subject areas

  • Genetics
  • General

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Independent β-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. / Wei, Huijun; Ahn, Seungkirl; Shenoy, Sudha K.; Karnik, Sadashiva S.; Hunyady, L.; Luttrell, Louis M.; Lefkowitz, Robert J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 19, 16.09.2003, p. 10782-10787.

Research output: Contribution to journalArticle

Wei, Huijun ; Ahn, Seungkirl ; Shenoy, Sudha K. ; Karnik, Sadashiva S. ; Hunyady, L. ; Luttrell, Louis M. ; Lefkowitz, Robert J. / Independent β-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 19. pp. 10782-10787.
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